2.1 Important Preparation and Administration Instructions

• There are two formulations, DEFINITY and DEFINITY RT, that have differences in preparation and storage. Ensure of the correct product when following the directions for preparation and storage.
• DEFINITY must be activated using the VIALMIX or VIALMIX RFID device before administration according to the instructions outlined below [see Dosage and Administration (2.5)].
• DEFINITY is for intravenous use only and must not be administered by intra-arterial injection [see Warnings and Precautions (5.3)].
• For adult patients, DEFINITY can be administered by either an intravenous bolus or infusion. The maximum dose is either two bolus doses or one single infusion. Do not administer the bolus and infusion dosing in combination or in sequence [see Dosage and Administration (2.2)].
• For pediatric patients, DEFINITY is administered by an intravenous bolus injection only. The maximum dose is two bolus doses [see Dosage and Administration (2.3)].

2.2 Recommended Dosage in Adult Patients

2.3 Recommended Dosage in Pediatric Patients

2.4 Imaging Instructions

2.5 Instructions for Activation, Preparation, and Handling of DEFINITY

1. Adhere to strict aseptic procedures during preparation.
2. Allow the DEFINITY vial to warm to room temperature before starting the activation procedure.
3. Activate DEFINITY by shaking the vial for 45 seconds using a VIALMIX device or VIALMIX RFID device.
   Note: Use only the drug activated in a properly functioning VIALMIX or VIALMIX RFID for a full 45 second activation cycle. Do not reactivate the vial if VIALMIX or VIALMIX RFID did not properly activate the vial. Never reactivate a successfully activated DEFINITY vial (see step 4). Refer to the VIALMIX or VIALMIX RFID User's Guide for illustrations of the activation procedure and a properly functioning VIALMIX or VIALMIX RFID.

4. Activated DEFINITY appears as a homogeneous milky white suspension with a presence of foam/bubbles. Use immediately after activation. If the product is not used within 5 minutes of activation, resuspend the microspheres by 10 seconds of hand agitation by inverting the vial before the product is withdrawn in a syringe.

5. The activated DEFINITY may be used for up to 12 hours from the time of activation, but only after the microspheres are resuspended by hand agitation for 10 seconds. Store the activated DEFINITY at room temperature 20° to 25°C (68° to 77°F) in the original product vial.
6. Invert the vial and withdraw the activated homogeneous milky white suspension using the Intellipin (Dispensing Pin), the PINSYNC (Vented Vial Adapter 13mm), or 18 gauge to 20 gauge syringe needle from the middle of the liquid. Do not inject air into the DEFINITY Vial.
7. Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe.
8. For infusion dosing in adult patients, dilute 1.3 mL of activated DEFINITY in 50 mL of preservative-free 0.9% Sodium Chloride Injection, USP.
9. Parenteral drug products should be inspected visually for foreign particulate matter and discoloration prior to administration, whenever solution and container permit.

2.6 Instructions for RFID-Tagged Vials

The radio frequency identification (RFID) tag integrated on the back of the vial label when used with VIALMIX RFID allows for the exchange of product information such as activation time and activation rate. If the RFID tag is damaged or otherwise non-functional, the vial with the non-functional RFID tag cannot be activated with VIALMIX RFID. Discard the non-functional RFID-tagged vial. Do not activate RFID-tagged DEFINITY vials in the VIALMIX RFID within 6 inches (15 cm) of a pacemaker and/or defibrillator (see the VIALMIX RFID User's Guide).

5.1 Serious Cardiopulmonary Reactions

Serious cardiopulmonary reactions including fatalities have occurred uncommonly during or shortly following perflutren-containing microsphere administration, typically within 30 minutes of administration. The risk for these reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias). Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY administration and monitor all patients for acute reactions.

The reported reactions include: fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, and convulsions [see Adverse Reactions (6.2)].

5.2 Hypersensitivity Reactions

In postmarketing use, serious hypersensitivity reactions were observed during or shortly following perflutren-containing microsphere administration including:

Anaphylaxis, with manifestations that may include death, shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema.

These reactions have occurred in patients with no prior exposure to perflutren-containing microsphere products. DEFINITY contains PEG. There may be increased risk of serious reactions including death in patients with prior hypersensitivity reaction(s) to PEG [see Adverse Reactions (6.2) and Description (11)]. Clinically assess patients for prior hypersensitivity reactions to products containing PEG, such as certain colonoscopy bowel preparations and laxatives. DEFINITY is contraindicated in patients with known or suspected hypersensitivity to perflutren lipid microsphere or its components such as PEG [see Contraindications (4)]. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY administration and monitor all patients for hypersensitivity reactions.

5.3 Systemic Embolization

When administering DEFINITY to patients with a cardiac shunt, the microspheres can bypass filtering by the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following DEFINITY administration. DEFINITY is only for intravenous administration and must not be administered by intra-arterial injection [see Dosage and Administration (2.1,2.2,2.3)].

5.4 Ventricular Arrhythmia Related to High Mechanical Index

High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. The maximum recommended mechanical index for use with DEFINITY is 0.8 in adult patients and 0.3 in pediatric patients [see Dosage and Administration (2.4)].

5.5 Pain Episodes in Patients with Sickle Cell Disease

In postmarketing reports, acute pain episodes shortly following DEFINITY administration have been reported in patients with sickle cell disease (SCD). The pain episodes included moderate to severe back pain and vaso-occlusive crisis [see Adverse Reactions (6.2)]. If a patient with sickle cell disease experiences new or worsening pain, discontinue DEFINITY.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of DEFINITY have been established for use in pediatric patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve delineation of the left endocardial border. Use of DEFINITY for this indication is supported by evidence from adequate and well-controlled studies in adults [see Clinical Studies (14)], a pharmacodynamic and safety study in 40 pediatric patients 1 month of age and older [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2)], and published studies in 149 patients 5 years to 24 years of age [see Adverse Reactions (6.1)].

8.5 Geriatric Use

Of the total number of subjects in clinical trials of DEFINITY, 144 (33%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences between the elderly and younger patients.

12.1 Mechanism of Action

Perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. These physical acoustic properties of activated DEFINITY provide contrast enhancement of the left ventricular chamber and aid delineation of the left ventricular endocardial border during echocardiography.

In animal models the acoustic properties of activated DEFINITY were established at or below a mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below a mechanical index of 0.8.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of perflutren gas was evaluated in healthy subjects (n=8) after the intravenous administration of activated DEFINITY at 50 microL/kg (5 times the recommended dose).

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies with activated DEFINITY have not been performed to evaluate carcinogenic potential. Evidence of genotoxicity was not found in the following studies with activated DEFINITY: 1) bacterial mutagenesis assay (Ames assay), 2) in vitro mammalian mutagenesis assay, 3) in vitro human lymphocyte chromosome aberration assay, and 4) in vivo rat micronucleus assay.

Impairment of male or female fertility was not observed in rats and rabbits treated with activated DEFINITY at doses up to 24 and 15 times the human dose based on body surface area (in rats and rabbits respectively).

Endocardial Border Length

As shown in Table 3, compared to baseline, a single bolus dose of 10 microL/kg of activated DEFINITY increased the length of endocardial border that could be measured at both end-systole and end-diastole. The mean change in border length from baseline at end-diastole was statistically significant for all readers in the apical 4-chamber view and for 3 out of 4 readers for the apical 2-chamber view. The mean change in border length from baseline at end-systole was statistically significant for 3 out of 4 readers for the apical 4-chamber view and for 2 out of 4 readers for the apical 2-chamber view.

Ventricular Chamber Enhancement

Left ventricular chamber enhancement after an activated DEFINITY dose of 10 microL/kg was significantly increased from baseline compared to placebo in both views at the mid-ventricular and apical levels at end-diastole. Similar results were noted at end-systole, with the exception of the 4-chamber view.

Wall Motion

In a retrospective analysis, in a subset of subjects (n=12 to 47, depending on reader) having at least 2 adjacent segments non-evaluable on non-contrast imaging, DEFINITY converted a baseline non-evaluable image to an evaluable image in 58 to 91% of the subjects, depending on the reader. In the converted images, the accuracy of wall motion (i.e., normal versus abnormal) improved in 42 to 71% of the subjects, depending on the reader, however, improvement in the specific diagnostic accuracy (e.g., hypokinetic, akinetic etc.) was not established. Also, in 13 to 37% of the subjects, depending on the reader, DEFINITY was found to obscure the wall motion rendering the image non-evaluable.

Ejection Fraction

In the 2 baseline controlled studies, ejection fraction results were evaluated in comparison to MRI. The results were evaluated by 3 blinded, independent radiologists. In these studies, although there was a statistically significant increase in ventricular chamber enhancement, DEFINITY did not significantly improve the assessment of ejection fraction compared to the baseline images.

How Supplied

DEFINITY (perflutren lipid microsphere) injectable suspension is supplied in a single- patient use clear glass vial or a single patient use clear glass Radio Frequency Identification (RFID)-tagged vial containing 6.52 mg/mL perflutren in the headspace of the vial and 0.75 mg/mL of a lipid blend in a clear, colorless liquid phase with 1.5 mL volume. DEFINITY is available in the following packages:

• One (1) vial or RFID-tagged vial per carton NDC (11994-011-01)
• Four (4) vials or RFID-tagged vials per carton - NDC (11994-011-04)
• Sixteen (16) vials or RFID-tagged vials per carton - NDC (11994-011-16)

Order VIALMIX or VIALMIX RFID from Lantheus Medical Imaging.

Storage and Handling

Before activation store between 2° to 8°C (36° to 46°F).

Regarding interference with medical devices, the RFID tag and VIALMIX RFID unit meets the IEC 60601-1-2 requirements for emission and immunity standards for medical devices.

Hypersensitivity Reactions

Advise patients to inform their healthcare provider if they develop any symptoms of hypersensitivity after DEFINITY administration, including rash, wheezing, or shortness of breath [see Warnings and Precautions (5.2)].